The hypothalamus is a small area at the base of the brain, weighing about 4 gm out of the 1400 gm brain weight of an adult human, yet it performs a wide range of functions that are vital for the survival of the individual. In general, the hypothalamus acts as a integrator to regulate and coordinate basic functions necessary for life, such as fluid and electrolyte balance; feeding and energy metabolism; wake-sleep cycles; thermoregulation; stress responses; and sexual behavior and reproduction.

Architecture of the hypothalamus

Located just behind and between the eyes, the anterior border of the hypothalamus is formed by the optic chiasm. It is bordered laterally by the optic tracts and temporal lobes, and the posterior limit of the hypothalamus, occupied by the mammillary bodies, is bounded by the cerebral peduncles. The hypothalamus, literally located below the thalamus, is divided in the midline by the third ventricle. It contains a series of reasonably well differentiated cell groups or nuclei, sandwiched between to major axonal pathways that connect it with the rest of the brain and with the endocrine system.

The periventricular axon system occupies the medial wall of the hypothalamus along the third ventricle, medial to most of the hypothalamic nuclei. It contains axons that connect the hypothalamus with the brainstem and thalamus. Some periventricular axons, from neurons that produce pituitary releasing hormones, travel to the median eminence, which is a vascular area in the floor of the third ventricle. Here they secrete the releasing hormones into the portal capillaries, which carry them to the anterior pituitary gland where they control secretion of prolactin, thyrotropin, corticotropin, growth hormone, gonadotropic hormones, and prolactin. Other periventricular axons, from cells in the supraoptic and paraventricular nuclei that produce oxytocin or vasopressin, pass directly through the pituitary stalk to the posterior pituitary gland, where their terminals secrete these hormones into the general circulation. Many of the neurons that produce releasing hormones are scattered along the wall of the third ventricle, mixed in with the periventricular system. However, at the base of the third ventricle there is a particularly large collection of such neurons, called the arcuate nucleus, and along the dorsal third ventricle is another such cluster in the paraventricular nucleus.

The lateral hypothalamic axon system, sometimes called the medial forebrain bundle, runs from rostral to caudal through the lateral hypothalamic area, serving to connect the more medial nuclei with the forebrain above, and with the brainstem below. Mixed in with the medial forebrain bundle are many relatively large neurons, whose axons frequently join the bundle, reaching as far rostrally as the cerebral cortex, and as far caudally as the spinal cord.

The medial integrative nuclei of the hypothalamus can roughly be divided into three groups from rostral to caudal. The most rostral nuclei, corresponding to the preoptic area, regulate fluid and electrolyte balance, body temperature, and sexual hormones . The brain’s biological clock, the suprachiasmatic nucleus, is also at this level, which sits just above the optic chiasm, as do neurons that are critical for causing sleep. The middle third of the hypothalamus contains the nuclei that regulate feeding, energy metabolism, stress responses, and coordinate all these with wake-sleep cycles. The caudal third of the hypothalamus contains neurons that are critical for maintaining wakefulness and responding to emergencies.

Blood supply of the hypothalamus

Strokes of the hypothalamus are vanishingly rare, as the hypothalamus has the most luxuriant blood supply in the brain, befitting a site that is absolutely critical to maintain life. The hypothalamus is what the circle of Willis circles. It is literally surrounded by the internal carotid and basilar arteries, and the blood vessels that connect them.

Inputs to the hypothalamus

The hypothalamus sits at a crossroads in the brain, receiving direct sensory inputs from the smell, taste, visual, and somatosensory systems. It also contains within it sensors for such things as blood temperature, blood sugar and mineral levels, and a variety of hormones. Thus the hypothalamus receives sensory inputs necessary to detect challenges in both the internal and external environments.

In addition, the hypothalamus receives inputs from forebrain areas including the hippocampus, amygdala, and cingulate cortex. These structures form the limbic lobe of the brain, which receives highly processed sensory information from throughout the cerebral cortex, and determines it personal importance for the individual. These inputs drive a wide range of emotional responses, and many of the phenomena we associate with emotional expression (changes in heart rate, blushing, hair standing on end, etc.) are mediated by the hypothalamus.

Homeostatic, allostatic, and circadian control systems

The hypothalamus protects the vital capacity of the organism in three critical ways. First, it must maintain a well regulated internal milieu of electrolyte concentrations and osmolality, glucose and other fuels, and body temperature. The intracellular biochemical machinery of the mammalian body is exquisitely adapted to this environment, and cannot tolerate even small alterations in it. When exposed to levels of sodium, for example, that are 10-15% too high or too low; to levels of glucose less than 50% of the optimum; or body temperatures 4-5 degrees C above or below the normal, there is substantial degradation of brain function. Similar alterations occur in other tissues, although perhaps with margins that are perhaps not quite so narrow as for the brain. The hypothalamus therefore normally maintains a homeostasis (Greek for “staying the same”) with electrolytes such as sodium generally held within 5% of optimum; glucose above levels that may cause impairment; and body temperature within a few tenths of degree of optimum. The hypothalamus accomplishes this by having neurons that either receive inputs from sensory systems that monitor these variables, or are themselves sensitive to them. These neurons attempt to regulate these parameters against what amounts to a setpoint, just as the thermostat in a home is adjusted to a setpoint.

In contrast to the homeostatic systems of the hypothalamus, other systems deal with large and unpredictable perturbations of the environment that require a change in behavior and physiology. These allostatic responses range from recognition of and appropriate adjustments to the presence on the one hand of a mate, and on the other hand of a life threatening attack. The responses can include resetting various setpoints (e.g., increase in body temperature and blood pressure), as well as endocrine adjustments (such as cortisol and adrenaline release when under threat), and of course include abrupt and dramatic alterations of behavior (from mating to fight or flight).

In addition to making adjustments of the internal milieu that support homeostasis, and responding to urgent external events, the hypothalamus also helps anticipate daily events that are triggered by the external day-night cycle. Whether animals are diurnal (awake in the day) or nocturnal (awake at night), they have predictable times for feeding, drinking, sleeping, and sexual behavior. All of these are regulated by the circadian timing system in the brain, so that the body anticipates its various demands and opportunities. For example, wakefulness and cortisol levels peaks at the time of day necessary for an animal to forage for food, while the setpoint for body temperature falls a full degree during the time of day when an animal sleeps.

To exert its control over so many bodily functions, the hypothalamus uses three major outputs: autonomic, endocrine, and behavioral systems. In autonomic control, the hypothalamus contains neurons the send axons directly to the preganglionic neurons for both the sympathetic and parasympatheticnervous systems. These autonomic control neurons are in the paraventricular and arcuate nuclei, and the lateral hypothalamic area. In addition the hypothalamus has extensive outputs to adjust brainstem circuits that regulate autonomic reflexes.

The hypothalamus controls the endocrine system in three ways. First, as described above, neurons in the paraventricular and supraoptic nuclei send their axons to form the posterior pituitary gland, where they secrete oxytocin and vasopressin. Second, neurons in the periventricular, paraventricular, and arcuate nuclei send axons to the median eminence, to secrete pituitary hormone releasing hormones, which regulate the anterior pituitary gland. Finally, the hypothalamus controls autonomic outputs to many peripheral endocrine tissues, which further regulate their secretion.

Hypothalamic control of behavior is mediated in several ways. First, the lateral hypothalamic area and the histaminergic tuberomammillary nucleus play a major role in determining the overall level of wakefulness or arousal. Second, hypothalamic inputs to various motor pattern generators may increase the probability of specific behaviors. For example when hungry, most animals need to forage for food, then explore it by licking and sniffing, and finally to consume it. The hypothalamus may reduce the threshold for activating motor pattern generators for locomotion, and for sniffing and oral behaviors that are involved in ingestion of food. Thus animals are more likely to encounter food and more likely to explore and consume it. Third, there are hypothalamic descending outputs to sensory systems that may sensitize them (e.g., when hungry, food tastes better) or desensitize them (e.g., when under threat, pain is not perceived as readily). Finally, hypothalamic control of autonomic responses may cause signals (stomach grumbling when hungry; dry mouth when thirsty) that reach conscious appreciation in higher cognitive systems as a need to engage in a behavior (in this case, eat or drink). Similarly, hypothalamic regulation of endocrine systems may feed back on the brain. For example, many neurons in the brain have receptors for steroid hormones involved in reproduction, stress responses, or salt depletion, and changes in these hormones may alter the likelihood of various complex behaviors regulated by those neuronal systems.

Hypothalamic control of fluid and electrolyte balance

To maintain adequate tissue perfusion, the hypothalamus must regulate fluid acquisition through drinking, and control the osmolality and electrolyte content of the blood, as well as the overall blood volume. When there is excess fluid volume, it must regulate diuresis by the kidney. These tasks are under the regulation of the preoptic area, in particular the median preoptic nucleus and organum vasculosum of the lamina terminalis, along the anterior wall of the third ventricle. Drinking behavior is tightly linked with feeding, and with thermoregulation (as many of the cooling strategies used by the brain involve heat loss via water evaporation).

Hypothalamic control of feeding and energy metabolism

The most common cause of death for most animals is starvation. To insure adequate energy stores, the hypothalamus must drive feeding behavior, and regulate metabolic rate. The conversion of fuel from sugars to fat during times of plenty, or of proteins to fuel in lean times, are under the control of hypothalamic autonomic and endocrine regulation. The control of feeding and energy metabolism is mainly accomplished by the arcuate nucleus, working with the ventromedial and dorsomedial nuclei, the paraventricular nucleus, and the lateral hypothalamus. The regulation of energy metabolism interacts with reproduction (because animals only can afford to reproduce when there is sufficient food to insure the survival of the offspring), thermoregulation (in times of starvation metabolic rate drops and body temperature is lower), and wake-sleep states (animals must be awake and alert to forage for food and will completely invert their wake-sleep cycles if food is only available during their normal sleep cycle).

Hypothalamic control of thermoregulation

Cellular biochemical reactions require that body temperature be tightly controlled. For example, by raising body temperature by 2 degrees C during an infection, the activity of white blood cells is increased, while most bacteria are less able to reproduce. This small advantage to the host can spell the difference between survival and death. Thermoregulation is controlled mainly by neurons in the median and medial preoptic nuclei, as well as the lateral preoptic area. In general, these neurons tend to inhibit a thermogenic region in the dorsomedial nucleus and paraventricular nucleus. The latter send excitatory inputs to brainstem cell groups that increase body temperature. So, when the hypothalamus is warmed, inhibitory neurons turn off this thermogenic system, and body temperature falls. Thermoregulation interacts with feeding (as energy is required to produce heat and increase metabolic rate), reproduction (as body temperature is affected by menstrual cycles), and wake-sleep cycles (as body temperature falls during sleep). When food stores are low, animals may enter a state of torpor, or hibernation, where their body temperature falls to about 30 degrees C, and the brain enters a sleep-like state. On the other hand, body temperature increases during stress.

Hypothalamic control of reproduction

In mammalian females, the hypothalamus maintains cycles of reproductive readiness. Animals do not enter this state (i.e., go through puberty) until they have achieved sufficient body energy stores, and in many species the correct time of the year, for breeding. Hypothalamic neurons in the periventricular region and arcuate nucleus produce reproductive hormones, and sexual behavior is influenced by the medial preoptic, the ventromedial, and the ventral premammillary nuclei. The preoptic area also appears to regulate autonomic control over the genitalia (penile erection, secretion of lubrication). Reproduction thus interacts with systems controlling adequate energy stores, fluid balance to insure blood supply to the developing fetus, and thermoregulation. It is also highly arousing.

Hypothalamic control of sleep and wakefulness

Neurons in the posterior half of the lateral hypothalamus as well as in the tuberomammillary nucleus, provide major inputs to the cerebral cortex and the basal forebrain that are concerned with alerting and arousal responses, and are critical for producing a fully awake state. These neurons, and others in the brainstem that promote wakefulness, are in turn under the influence of a master switch, the ventrolateral preoptic nucleus, which inhibits the components of the arousal system during sleep, and is necessary for normal sleep states to occur. The wake sleep system, including neurons in the lateral hypothalamus containing the peptide orexin, is in turn under the control of the circadian system. The dorsomedial nucleus, which receives circadian timing signals from the suprachiasmatic nucleus, seems to play critical role in coordinating the two. Sleep-wake regulation interacts with feeding, drinking, and sexual and defensive behavior, all of which, of course, require a waking state. There is also a strong interaction between sleep and thermoregulation.

Hypothalamic control of stress responses

When an animal is under attack, it must reach full arousal, mobilize its energy stores, and be ready either for fight or flight. Reproductive behavior, food foraging, and other non-essential tasks must be inhibited. The signals that regulate this response must come from cognitive and limbic systems that are capable of assessing threats. The paraventricular nucleus plays a key role in stress responses, as it contains most of the neurons that produce corticotropin releasing hormone, which causes release of ACTH and then adrenal steroids. The paraventricular nucleus also contains many of the autonomic control neurons, necessary to cause adrenaline release. However, lateral hypothalamic neurons must be engaged to bring the cortex to a full state of alert wakefulness, as must medial hypothalamic neurons to mobilize energy stores. Stress inhibits sexual behavior, and in some cases may even lead to interruption of pregnancy. Because stress is inherently non-specific, i.e., it can include any stimulus that threatens survival, it may inherently interact with any of the other hypothalamic regulatory systems.